Acute and chronic pain imposes a tremendous burden on society, not only because of the associated human suffering, but also the cost of medical treatment, loss of productivity and disability payments, which has been estimated to be up to $650 billion per year in the USA alone. Current treatments for pain are hampered by limited efficacy and acute or long-term side effects. Acetaminophen is an important drug in the management of pain; however, overdose (which is quite common) can lead to liver damage, subsequent liver failure, and even death. A safe non-liver toxic drug, with equal or improved efficacy compared to acetaminophen, would be a ground breaking new product for the treatment of pain. Kalyra Pharmaceuticals has synthesized a number of structurally related acetaminophen analogs, utilizing our toolbox of proprietary bioisosteres, and discovered new highly potent analgesic compounds that do not form a toxic metabolite. With proof of concept in hand, further development of these analogues is the subject of this direct to Phase II proposal, via the Specific Aims outlined below: Phase II: Non-Clinical Development of a New Treatment for Pain Aim 1. Further Characterization of Efficacy and In Vivo Pharmacology Aim 2. ADMET, Additional Pharmacology and Preliminary Toxicology Aim 3. Pharmacokinetic Studies to Confirm Second Species Selection for Safety Aim 4. Non-Clinical Toxicology Studies in Support of Filing of an IND After completion of the IND-enabling studies outlined in this proposal, we anticipate the filing of an IND with the FDA to begin human clinical trials for the development of a novel, safe, effective and non-addictive new treatment for the management of pain.